Neuropilin-1 high monocytes protect against neonatal inflammation

Neonates are susceptible to inflammatory disorders such as necrotizing enterocolitis (NEC) due to their immature immune system. The timely appearance of regulatory immune cells in early life contributes to the control of inflammation in neonates, the underlying mechanisms of which remain poorly understood. In this study, we identified a subset of neonatal monocytes characterized with high levels of neuropilin-1 (Nrp1), termed Nrp1 high monocytes. Nrp1high monocytes displayed potent immunosuppressive activity as compared with their Nrp1low counterpart. Nrp1 deficiency in myeloid cells aggravated the severity of NEC, whereas adoptive transfer of Nrp1 highmonocytes led to remission of NEC. Mechanistic studies showed that Nrp1, via binding to its ligand Sema4a, induced intracellular p38-MAPK/mTOR signaling and activated the transcription factor KLF4. KLF4 transactivated Nos2 and enhanced the production of nitric oxide (NO), a key mediator of immunosuppression in monocytes. These observations uncover an important immunosuppressive axis in neonatal monocytes and provide a potential therapeutic strategy for inflammatory disorders in neonates. Overall design: In this study, we investigated whether Nrp1 contributes to the immunosuppression in neonates. By profiling Nrp1 expression in distinct type of immune cells fromneonatal mice, we identified a subset of monocytes with high Nrp1 expression named Nrp1high monocytes. Nrp1high monocytes displayed potent immunosuppressive activity and declined in age-dependent manner. Mechanistic studies showed that upon ligation with its receptor Sema4a, Nrp1 induced intracellular p38-MAPK/mTORC1 signaling and the activation of the transcription factor Klf4. KLF4 transactivated the expression of Nos2 and enhanced the production of NO. Combination of conditional knockout mice and adoptive transfer experiments, we demonstrated that Nrp1high monocytes protected against inflammatory disease NEC in neonatal mice. These observations provide insights into the immunosuppressive function of neonatal monocytes, which may have therapeutic value in the control of inflammation in early life.